Process for the preparation of substituted octanoyl amides

ABSTRACT

Compounds of formula (II) are simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the halolactone is converted into a hydroxylactone and then the hydroxy group into a leaving group, the leaving group is replaced with azide, the lactone amidated and then the azide converted to the amine group, in order to obtain compounds of formula (I).

[0001] The invention relates to a process for the preparation of2(S),4(S),5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides and their physiologically acceptable salts; and the new compoundsused as intermediates in the multistage process.

[0002] In EP-A-0 678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarbox-amidesare described, which exhibit renin-inhibiting properties and could beused as antihypertensive agents in pharmaceutical preparations. Themanufacturing procedures described are unsatisfactory in terms of thenumber of process steps and yields and are not suitable for anindustrial process. A disadvantage of these processes is also that thetotal yields of pure diastereomers that are obtainable are too small.

[0003] It has now been surprisingly found that these alkane-carboxamidescan be prepared both in high total yields and in a high degree ofpurity, and that selectively pure diastereomers are obtainable, if thedouble bond of 2,7-dialkyl-8-aryl-4-octenic acid or2,7-dialkyl-8-aryl-4-octenic acid ester is simultaneously halogenated inthe 5 position and hydroxylated in the 4 position under lactonization,the halolactone is converted to a hydroxylactone and then the hydroxygroup is converted to a leaving group, the leaving group substitutedwith azide, the lactone amidated and then the azide converted to theamine group. Apart from the high yields and stereoselectivities in theindividual process steps, particular attention is drawn to the fact thatsubstantially fewer by-products are formed in the azidation step.

[0004] A primary object of the invention is a process for thepreparation of compounds of formula I,

[0005] wherein

[0006] R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ isC₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl,C₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,C₁-C₆alkylamino-C₁-C₆-alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl,C₁-C₆-alkanoylamido-C₁-C₆-alkyl, HO(O)C—C₁-C₆-alkyl,C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, H₂N—C(O)—C₁-C₆alkyl,C₁-C₆alkyl-HN—C(O)—C₁-C₆alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl,comprising

[0007] a) the reaction of a compound of formula II,

[0008] with an amine of formula R₅—NH₂ to form a compound of formulaIII,

[0009] and

[0010] b) reduction of the azide group of the compound of formula III tothe amine group and isolation of the compounds of formula I, ifnecessary with the addition of a salt-forming acid, comprising thepreparation of compounds of formula II by reacting

[0011] c1) a compound of formula IV,

[0012] wherein R₆ is C₁-C₂₀alkyl, C₃-C₁₂cycloalkyl,C₃-C₁₂cycloalkyl-C₁-C₆alkyl, C₆-C₁₀aryl or C₆-C₁₀-aryl-C₁-C₆alkyl, witha halogenation agent to form a compound of formula VI, or

[0013] c2) a carboxylic acid of formula V, or a salt of this carboxylicacid,

[0014] with a halogenation agent to form a compound of formula VI,

[0015] wherein X is Cl, Br or I,

[0016] d) reaction of the compound of formula VI in the presence of analkali metal or alkaline earth metal hydroxide or an alcohol to form acompound of formula VII,

[0017] wherein M is an alkali metal, an equivalent alkaline earth metalor the residue of an alcohol minus a hydroxyl group,

[0018] e) hydrolysis of the compound of formula VII in the presence ofan acid to form a compound of formula VIII,

[0019] f) substitution of the hydrogen atom of the hydroxyl group in thecompound of formula VIII and conversion thereof to a leaving group AO toform compounds of formula IX,

[0020] g) and then reaction of the compound of formula IX with anazidation agent to form a compound of formula II, or

[0021] h) reaction if the compound of formula VIII directly with a zincazide/-bis-pyridine complex in the presence of a tertiary phosphine andan azodicarboxylate, if necessary in an organic solvent, to form acompound of formula II.

[0022] As an alkyl, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl,n-, i- and t-butyl, pentyl and hexyl.

[0023] As a halogenalkyl, R₁ and R₂ may be linear or branched andpreferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examplesare fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

[0024] As an alkoxy, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

[0025] As an alkoxyalkyl, R₁ and R₂ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms,and the alkyl group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl,methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl,1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl,propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and1-butyloxyeth-2-yl.

[0026] As a C₁-C₆alkoxy-C₁-C₆alkyloxy, R₁ and R₂ may be linear orbranched. The alkoxy group preferably comprises 1 to 4 and especially 1or 2 C atoms, and the alkyoxy group preferably comprises 1 to 4 C atoms.Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy,1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy,methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy,1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy,ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy,1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.

[0027] In a preferred embodiment, R₁ is methoxy- orethoxy-C₁-C₄alkyloxy, and R₂ is preferably methoxy or ethoxy.Particularly preferred are compounds of formula I, wherein R₁ is1-methoxyprop-3-yloxy and R₂ is methoxy.

[0028] As an alkyl, R₃ and R₄ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl,n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R₃ andR₄ in compounds of formula I are in each case isopropyl.

[0029] As an alkyl, R₅ may be linear or branched in the form of alkyland preferably comprise 1 to 4 C atoms. Examples of alkyl are listedhereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl arepreferred.

[0030] As a C₁-C₆hydroxyalkyl, R₅ may be linear or branched andpreferably comprise 2 to 6 C atoms. Some examples are2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.

[0031] As a C₁-C₆alkoxy-C₁-C₆alkyl, R₅ may be linear or branched. Thealkoxy group preferably comprises 1 to 4 C atoms and the alkyl grouppreferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl,2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl,2-ethoxyethy-1-yl, 2-ethoxyprop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or4-ethoxybut-1-yl.

[0032] As a C₁-C₆alkanoyloxy-C₁-C₆alkyl, R₅ may be linear or branched.The alkanoyloxy group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 2 to 4 C atoms. Some examples are formyloxymethyl,formyloxyethyl, acetyloxy-ethyl, propionyloxyethyl and butyroyloxyethyl.

[0033] As a C₁-C₆aminoalkyl, R₅ may be linear or branched and preferablycomprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.

[0034] As C₁-C₆alkylamino-C₁-C₆alkyl and C₁-C₆dialkylamino-C₁-C₆-alkyl,R₅ may be linear or branched. The alkylamino group preferably comprisesC₁-C₄alkyl groups and the alkyl group preferably 2 to 4 C atoms. Someexamples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl,2-ethylaminoeth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl,3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and4-dimethylaminobut-1-yl.

[0035] As a C₁-C₆alkanoylamido-C₁-C₆alkyl, R₅ may be linear or branched.The alkanoyl group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl,2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and4-butyroylamidoeth-1-yl.

[0036] As a HO(O)C—C₁-C₆alkyl, R₅ may be linear or branched and thealkyl group preferably comprises 2 to 4 C atoms. Some examples arecarboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

[0037] As a C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, R₅ may be linear or branched,and the alkyl groups preferably comprise independently of one another 1to 4 C atoms. Some examples are methoxycarbonylmethyl,2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl,4-methoxycarbonylbut-1-yl, ethoxycarbonylmethyl,2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl-prop-1-yl, and4-ethoxycarbonylbut-1-yl.

[0038] As a H₂N—C(O)—C₁-C₆alkyl, R₅ may be linear or branched, and thealkyl group preferably comprises 2 to 6 C atoms. Some examples arecarbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl,2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl,3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl,3-carbamido-3-ethylprop-1-yl, 3-carbamido-2,2-dimethylprop-1-yl, 2-, 3-,4- or 5-carbamidopent-1-yl, 4-carbamido-3,3- or -2,2-dimethylbut-1-yl.

[0039] As a C₁-C₆alkyl-HN—C(O)—C₁-C₆-alkyl or(C₁-C₆alkyl)₂N—C(O)—C₁-C₆alkyl, R₅ may be linear or branched, and theNH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl grouppreferably 2 to 6 C atoms. Examples are the carbamidoalkyl groupsdefined hereinabove, whose N atom is substituted, with one or twomethyl, ethyl, propyl or butyl.

[0040] A preferred subgroup of compounds of formula I is that in whichR₁ is C₁-C₄alkoxy or C₁-C₄alkoxy-C₁-C₄alkyloxy, R₂ is C₁-C₄alkoxy, R₃ isC₁-C₄alkyl, R₄ is C₁-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl which ifnecessary is N-monosubstituted or N-di-C₁-C₄alkyl substituted.

[0041] A more preferred subgroup of compounds of formula I is that inwhich R₁ is methoxy-C₂-C₄-alkyloxy, R₂ is methoxy or ethoxy, R₃ isC₂-C₄alkyl, R₄ is C₂-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl.

[0042] An especially preferred compound of formula I is that in which R₁is 3-methoxy-prop-3-yloxy, R₂ is methoxy, R₃ and R₄ are1-methyleth-1-yl, and R₅ is H₂NC(O)—[C(CH₃)₂]—CH₂—.

[0043] As an alkyl, R₆ may be linear or branched and comprise preferably1 to 12 C atoms, 1 to 8 C atoms being especially preferred. R₆ isparticularly preferred as a linear C₁-C₄alkyl. Some examples are methyl,ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl andeicosyl. Especially preferred are methyl and ethyl.

[0044] As a cycloalkyl, R₆ may preferably comprise 4 to 8 ring-carbonatoms, 5 or 6 being especially preferred. Some examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclododecyl.

[0045] As a cycloalkyl-alkyl, R₆ may comprise preferably 4 to 8ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1to 4 C atoms in the alkyl group, 1 or 2 C atoms being especiallypreferred. Some examples are cyclopropyl methyl, cyclobutyl methyl,cyclopentyl methyl or cyclopentyl ethyl, and cyclohexyl methyl orcyclohexyl ethyl.

[0046] As an aryl, R₆ is preferably phenyl or naphthyl.

[0047] As an aralkyl, R₆ is preferably benzyl or phenyl ethyl.

[0048] In formula VII, M may be an alkaline earth metal, for example Mg,Ca or Sr. Equivalent in the context of the invention means the chargeequalization of cation and anion. M is preferably an alkali metal, forexample Li, Na or K. Particular preference is for M as Li. If M is theresidue of an alcohol minus a hydroxyl group, it may be the R₆ group,including the embodiments and preferences described hereinbefore, inparticular alkyl and cycloalkyl.

[0049] Residue A in the leaving group AO is preferably the residue of anorganic acid, for example C₁-C₈acyl, particular preference being forC₁-C₈sulfonyl. The acyl residue may be a carboxylic acid, such as formicacid, acetic acid, propionic acid, butyric acid and benzoic acidsubstituted if necessary with C₁-C₄alkyl, C₁-C₄alkoxy or halogen. Thesulfonyl residue A may correspond for example to formula R₇—SO₂—,wherein R₇ is C₁-C₈alkyl, C₁-C₈halogenalkyl, C₃-C₈cycloalkyl, or phenylor benzyl either unsubstituted or substituted with C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄hakogenalkyl or halogen. Some examples of sulfonylresidues are methyl, ethyl, phenyl, methylphenyl, dimethyl phenyl,trimethyl phenyl, trifluoromethyl phenyl, chlorophenyl, dichlorophenyl,bromophenyl, dibromophenyl and trifluoromethyl sulfonyl.

[0050] The individual process steps may be carried out in the presenceof solvent. Suitable solvents are water and organic solvents, especiallypolar organic solvents, which can also be used as mixtures of at leasttwo solvents. Examples of solvents are hydrocarbons (petroleum ether,pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene,xylene), halogenated hydrocarbon (dichloromethane, chloroform,tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether,tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether);carbonic esters and lactones (methyl acetate, ethyl acetate, methylpropionate, valerolactone); N,N-substituted carboxamides and lactams(dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones(acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones(dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols(methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol,hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethylcyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol,propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether,and diethylene glycol monomethyl or monoethyl ether; nitriles(acetonitrile, propionitrile); tertiary amines (trimethylamine,triethylamine, tripropylamine and tributylamine, pyridine,N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organicacids (acetic acid, formic acid).

[0051] Process Step a)

[0052] The reaction of compounds of formula II to form compounds offormula III with a compound R₅NH₂ by opening of the lactone ring can becarried out with or without solvent. The reaction is expediently carriedout in the presence of alcohols or amines, which can form activatedcarbonic esters or carboxamides. Such compounds are well-known. Thesemay be 2-hydroxypyridine, N-hydroxycarboxamides and imides, andcarboximides (N-hydroxysuccinimide). Organic solvents are used assolvent, tertiary amines being of advantage, for example trimethylamineor triethylamine. The reaction temperature may range for example fromapproximately 40° C. to 150° C. and preferably from 50° C. to 120° C.

[0053] Process Step b)

[0054] Reduction of the azide group to the amine group in the compoundsof formula III takes place in a manner known per se (see ChemicalReviews, Vol. 88 (1988), pages 298 to 317), for example using metalhydrides or more expediently using a catalytic method with hydrogen inthe presence of homogeneous (Wilkinson catalyst) or heterogeneouscatalysts, for example Raney nickel or precious metal catalysts such asplatinum or palladium, if necessary on substrates such as carbon. Thehydrogenation can also be carried out if necessary catalytically underphase transfer conditions, for example with ammonium formate as hydrogendonor. It is of advantage to use organic solvents. The reactiontemperature may range for example from approximately 0° C. to 200° C.and preferably from 10° C. to 100° C. Hydrogenation may be carried outat normal pressure or increased pressure up to 100 bar, for example, andpreferably up to 50 bar.

[0055] The compounds of formula I may be converted to addition salts ina manner known per se by treatment with monobasic or polybasic,inorganic or organic acids. Hemifumarates are preferred.

[0056] Process Step c1)

[0057] Suitable chlorination, bromination and iodination agents areelemental bromine and iodine, in particular N-chlorine, N-bromine andN-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromoand N-iodophthalimide and especially chloro, N-bromo andN-iodosuccinimide, as well as tertiary butyl hypochlorite andN-halogenated sulfonamides and sulfonimides, for example chloramine T.The reaction is advantageously carried out in organic solvents misciblewith water, such as tetrahydrofuran or dioxane in the presence of atleast an equivalent volume of water. The reaction takes place first atlow temperatures, for example −20 to 10° C., and then at elevatedtemperatures, for example 30 to 100° C. The presence of inorganic ororganic acids may be advantageous. Suitable acids are for example formicacid, acetic acid, methanesulfonic acid, trifluoroacetic acid,trifluoromethanesulfonic acid, toluenesulfonic acid, H₂SO₄, H₃PO₄,hydrogen halides, acid ion exchange resins, and acids immobilized onsolid carriers. The halolactone may be isolated for example byextraction with organic solvents.

[0058] Process Step c2)

[0059] Suitable chlorination, bromination and iodination agents areelemental bromine and iodine, in particular N-chloro, N-bromo andN-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromoand N-iodophthalimide and especially chloro, N-bromo andN-iodosuccinimide, as well as tertiary butyl hypochlorite andN-halogenated sulfonamides and sulfonimides, for example chloramine T.The reaction is advantageously carried out in organic solvents, such ashalogenated hydrocarbons (chloroform, dichloromethane). The reactiontemperature may range for example from approximately −70° C. to ambienttemperature and preferably from −30° C. to 10° C. The halolactone may beisolated for example by extraction with organic solvents.

[0060] Suitable salts of carboxylic acids of formula V are for examplealkali metal or alkaline earth metal salts, for example sodium,potassium, magnesium or calcium salts, as well as ammonium salts. Theammonium salts may derive from ammonia, primary, secondary or tertiaryamines, or they may e quaternary ammonium salts. The amines may beacyclic or cyclic and comprise heteroatoms from the C and S group. Theamines may comprise 1 to 18 C atoms, 1 to 12 being preferred and 1 to 8especially preferred. Quaternary ammonium salts may comprise 4 to 18 Catoms, 4 to 12 being preferred and 4 to 8 especially preferred. Someexamples of amines are methylamine, dimethylamine, triethylamine,ethylamine, diethylamine, triethylamine, propylamine, dipropylamine,Tripropylamine, isopropylamine, butylamine, dibutylamine, tributylamine,phenylamine, methylethylamine, methyldiethylamine, phenylmethylamine,benzylamine, cyclopentylamine, cyclohexylamine, piperidine,N-methyl-piperidine, morpholine, pyrrolidine, and 2-phenylethylamine.Salt formation allows a more efficient purification of the carboxylicacids of formula V with regard to their optical and chemical purity,especially when crystalline salts are formed with the selection ofamines. The salts may be converted before the reaction to the carboxylicacids of formula V. However, the salts may also be used directly forhalolactonization. In this case, the addition of acids, for exampletrifluoroacetic acid or other strong acids, is recommended, as describedunder process step c1).

[0061] The halolactonization is surprisingly stereoselective, and thedesired cis-halolactones are formed in yields of up to 90% or more.

[0062] Process Step d)

[0063] The reaction of a compound of formula VI with at least equimolarquantities of alkali or alkaline earth metal hydroxides is expedientlycarried out in a polar organic solvent, for example alcohols such asisopropanol, and at low temperatures of, for example, −20 to 30° C.Aqueous solutions of hydroxides are preferably used, lithium hydroxidebeing especially preferred. The compound of formula VII does not need tobe isolated, but the reaction mixture can be used directly in processstep e). The desired stereoisomer is also formed in this step at highyields of up to 90% or more.

[0064] The reaction of a compound of formula VI with at least equimolarquantities of an alcohol, especially a C₁-C₈alkanol and in particularmethanol or ethanol, is expediently carried out in a polar organicsolvent, for example ethers or the alkanols used for esterification, andat low temperatures of, for example −20 to 30° C. Bases are preferablyused as well, for example alkali metal hydrogencarbonates or alkalimetal carbonates, potassium hydrogencarbonate being especiallypreferred. The compound of formula VII does not need to be isolated, butthe reaction mixture can be used directly in process step e). Thedesired stereoisomer is also formed in this reaction at high yields ofup to 90% or more.

[0065] Process Step e)

[0066] Lactonization of the compounds of formula VII to form compoundsof formula VIII is expediently carried out at a temperature of −20 to50° C. and in the presence of a preferably polar solvent, such as analcohol (isopropanol) or ether (tetrahydrofuran, dioxane). It isadvantageous to use inorganic acids, especially mineral acids such ashydrochloric acid, hydrobromic acid or sulfuric acid. The hydroxylactoneof formula VII may be isolated for example by extraction with organicsolvents. The desired stereoisomer is also formed in this step at highyields of up to 90% or more.

[0067] Process Step f)

[0068] Conversion of the hydroxy group to a leaving group may be carriedout in organic solvents, preferably polar organic solvents, and attemperatures of −20 to 50° C. Acid halogenides, such as acid chloridesand acid bromides, are preferably used as reagents. Sulfonyl chloridesor bromides are especially preferred. The reaction is advantageouslycarried out in the presence of equivalent quantities of a base forbonding of the acid. Suitable bases are in particular tertiary amines,such as trimethylamine or triethylamine and dimethylaminopyridine. Thehydroxylactone of a compound of formula VII may be isolated for exampleby extraction with organic solvents. The yields are up to 90% or more.

[0069] Process Step g)

[0070] Suitable azidation agents are for example metal azides,especially alkaline earth metal azides and alkali metal azides, as wellas silyl azides. Especially preferred azidation agents are lithiumazide, sodium azide and potassium azide. The reaction may be carried outin organic solvents, such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylformamide(DMF), 1,3-dimethylimidazolidinone (DMI), toluene or methylcyclohexane.The reaction temperature may range for example from approximately 20° C.to 150° C. and preferably from 50° C. to 120° C. It may be expedient toinclude the use of phase transfer catalysts. The preparation andsynthetic use of azides are described for example by E. F. V. Scriven inChemical Reviews, Vol. 88 (1988), pages 298 to 317 The yield amounts toan outstanding 70% or more.

[0071] In one variant, the introduction of the leaving group in processstep f) and the azidation in process step g) may be carried outsimultaneously in one reaction vessel.

[0072] Process Step h)

[0073] In one variant, the azidation may also be carried out directlywith the hydroxyl compound of formula VIII. This reaction has beendescribed by David. L. Hughes in Organic Preparations and ProceduresInt. (1996), 28 (2), pp. 127-164 and by M. C. Viaud et al. in Synthesis(1990), pp. 130 to 131. The azidation is carried out with at leastequimolar quantities of zinc azide/bis-pyridine in the presence of, forexample, triphenylphosphine in quantities of 2 equivalents or more, andapproximately equal quantities of an azodicarboxylate such asazodiisopropylcarboxylate. The reaction is carried out in an organicsolvent, especially an aromatic hydrocarbon, such as benzene, toluene orxylene. The reaction temperature may be −20 to 80° C.

[0074] Some intermediates prepared using the process according to theinvention are new and represent further objects of the invention.

[0075] A further object of the invention is thus a compound of formulaX,

[0076] wherein

[0077] R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ isC₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl,C₁-C₅alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,C1-C6alkylamino-C₁-C₆-alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl,C₁-C₆-alkanoyl-R_(Cl-Csalkanoyloxy-Cl- C)6alkyl, C1-C6aminoalkylamnoC3.-c6-alkyl, C1-C6-dialkylai 1., -C6-alkanoyl-amido - C -C6-al kyl,6-lyl, C, -C6alkyl -O- (0)C-C, -s - C6alk C6alkyl, C₁-C₆alkyl-HN-C(0)-C₁-C₆alkyl or

[0078] R₈ is hydrogen or R₈O is a leaving group.

[0079] For residues R₁, R₂, R₃, and R₄ in compounds of formula X, theembodiments and preferences described hereinbefore apply.

[0080] XI,

[0081] wherein

[0082] X is halogen and Rg is a residue of form a

[0083] and

[0084] R₁ and R₂ are, inde ndently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, ₁-Csalkoxy, C₁-C₆alkoxy-Cl7C₆alkyl, orC₁-C6alkoxy-C₁-0₆a1 loxy, R3 is C₁-Calkyl, R₄ is C₁-C₆alkyl, and R₅ isCl-C.a yl, C₁-C₆hydroxyalkyl, Cl-Cfalkoxy-C₁-C₆-alkyl, C₁-C₆alkanooxy-C₁-C₆alkyl, C₁-C₆aminoalkyvl C₁-C₆alkylamino-C₁-C₆-al#,1,C₁-C₆-dialkylamino-C₁-C6-alkylEC1-C₆-alkanoyl-amido ₁-C₆-alkyl,HO(0)C-C₁-C₆-alkyl, Ci C6alkyl-0-(0)C-C-C₆ yl, H₂N-C (0) -C₁-C₆alkyl,C₁-C₆alkyl -HN-C(0) C₁-C₆alkyl or

[0085] compounds of formula XI, the embodiments and prefere describedhereinbefore apply.

[0086] An object of the invention is also a compound of formula XII,

[0087] wherein

[0088] R₂₀ is a residue of formula

[0089] and

[0090] R₁ and R₂ are, indepen ently of one another, H, Cl-Calkyl,C₁-C₆halogenalkyl, CC lalkoxy, O₁-C₆alkoxy-C₁-C₆alkyl, orCl-C₆alkoxy-CL-C₆alkyloy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R5 isCL-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-CL-C₆-alkyl, C₁-C₆alkanoyloxyC r-C₆alkyl, C1-C6aminoalkyl, C₁-C₆alkylamino-C₁-C₆-alkyl,O₁-C₆-dialkylamino-C₁-C₆-alkyl, C₁-C₆-alkanoyl-amido-CC₆- ikyl, HO (0)C-C₁-C₆-alkyl, C₁-C₆alkyl-O- (0)C-Cl-C₆alkyl, -CN-C(O)l-O-C₆alkyl,C1-C6alkyl-HN-C(O)-C1-C6alkyl or (0₁C₆al l)₂N-C(O) -C₁-C₆-alkyl. Foresidues R₁, R₂, R₃, and R₄ in compounds of formula XII, t embodimentsand preferences described hereinbefore 4 pply. .

[0091] An object of the invention in a broader sense is a compound offormula VII,

[0092] wherein M is an alkali metal, an equivalent alkaline earth metalor the residue of an alcohol minus a hydroxyl group, and

[0093] R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₃-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, andC₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl,amino-C1-C6-alkyl,C1-C6-dialkylam l Cl-Cr,-alkanoyl-amido-C1-C6-alkyl, HO.-c - a lk,C1-C6alkyl-0- (0)C-Cl-C6a -Calkyl, C₁-C₆alkyl-HN-C (0) -C₁-C₆alkyl or.

[0094] For residues R₁, R₂, R₃, and R₄, as well as for M, in compoundsof formula VII, the embodiments and preferences described hereinbeforeapply.

[0095] An object of the invention is a compound of formula XIII

[0096] wherein R₁₁ is an alkali metal, an equivalent alkaline earthmetal, hydrogen or the residue of an alcohol minus a hydroxyl group, and

[0097] R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, alkyl,C₁-C₆alkanoyloxy-C₁-C₆alkyl, Cl- Ci C6alkylamino-C₁-C₆-alkyl, c_(l)-c₆-mino-C₁-C6-alkyl, CL-C₆-alkanoylamido-Cl- l O H(O)C-C₁-C₆-alkyl,C₁-C₆alkyl-O-(0) C i- H₂N-C (0) -C₁-C₆alkyl, C₁-C₆alkyl-HN-C (0) -C₁

[0098] For residues R₁, R₂, R₃, R₄, and R₁₁ in compounds of formulaXIII, the embodiments and preferences described hereinbefore apply.

[0099] The carboxylic acids of formula V used in process step c) may beprepared in a manner known per se by hydrolysis of hydrolysable acidderivatives such as carbonic esters, carbooxamides or carboxylates. Thehydrolysis may be carried out with acids or bases. Hydrolysis with abase is preferred, for example with alkali metal hydroxides (LIOH, KOHand NaOH), which can be added as aqueous solution or as a solid. Thereaction is advantageously carried out in water, organic solvents(alcohols and ethers) or mixtures thereof. The reaction temperature mayrange up to the boiling temperature of the solvent used. After removalof the solvent, the residue of the reaction is expediently taken up withan aqueous acid, such as hydrochloric acid, and the compound of formulaV is extracted (for example with ethers) and purified. The hydrolysis isquantitative, and the pure compound of formula V is obtained in yieldsof more than 90%. It is possible to carry out the hydrolysis at the sametime as the halolactonization in one reaction vessel. The hydrolysis mayalso be carried out enzymatically.

[0100] The compounds of formula XIII are obtainable by reacting acompound of formula XIV

[0101] with a compound of formula XV,

[0102] wherein R₁ to R₄, and R₁₁ are as defined hereinbefore, includingthe preferences, Y is Cl, Br or I, and Z is Cl, Br or I, in the presenceof an alkali metal or alkaline earth metal. Y and Z are preferably Brand especially Cl.

[0103] The coupling of Grignard reagents with alkenyl halogenides in anether such as tetrahydrofuran or dioxane as solvents in the presence ofcatalytic quantities of a soluble metal salt or metal complex, forexample an iron, nickel or palladium salt or an iron, nickel orpalladium complex (such as iron trichloride, iron acetonyl acetate ironbenzoyl acetonate, nickel acetonyl acetate, and iron, nickel orpalladium complexes with tertiary phosphines or ditertiary diphosphinessuch as triphenylphosphine, tricyclohexylphosphine, 1,2-diphenylphosphinoethane, 1, 2-diphenylphosphinopropane, 1,2-diphenylphosphinofuran, and 1, 2-diphenylphosphinobutane is known.Examples of metal complexes and metal complex salts aredichloronickel(1,2-diphenylphosphinoethane) anddichloropalladium(1,2-diphenylphosphinoethane). The presence of anadditive stabilizing the metal salts or metal complexes and metalcomplex salts- can be of advantage. Examples are DMPU,N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-morpholine, amines such as triethylamine andtetramethylethylenediamine, as well as mixtures of at least two of theseadditives. When using iron acetonylacetate, the addition of a mixture ofDMPU and tetramethylethylendiamine has proved successful. When usingdichloronickel(1,2-diphenylphosphinoethane), the addition oftriethylamine has proved to be of advantage.

[0104] The reaction is described by G. Cahiez et al. in Synthesis(1998), pp. 1199-1200. The reaction temperature may for example be −50to 80° C., preferably −20 to 50° C. Catalytic quantities may for examplebe 0.1 to 20% by weight in relation to a compound of formula XIV. It isexpedient to carry out the reaction so that initially a compound offormula XIV is converted to a Grignard compound (for example withmagnesium) and then adding a solution of a compound of formula XV, metalsalt, metal complex, or metal complex salt and the stabilizing additive,or vice versa.

[0105] It may be of advantage if only catalytic quantities of anadditive stabilizing the metal complexes, for example triethylamine orDMPU, are used. Catalytic quantities may for example be 0.1 to 10 molpercent, preferably 1 to 5 mol percent, in relation to compounds offormula XIV or XV.

[0106] Compounds of formula XIV in the form of their racemates orenantiomers are known or capable of being prepared according toanalogous processes. For example, RIR₂phenylaldehyde may be reacted withR₃diethoxyphosphorylacetic acid ester to form 2-R₃-3-(R₁R₂phenyl)acrylicacid esters, these may then be hydrogenated to form the correspondingpropionic acid esters, the ester group saponified and the carboxylicacid reduced to alcohol, and finally the hydroxyl group substituted withhalogen. Enantiomers are obtainable by separating the racemates of thecarboxylic acids with for example quinine or by enzymatic resolution ofthe racemates of the corresponding carbonic esters. Details aredescribed in the examples. A possible asymmetric synthesis of compoundsof formula XIV is described in EP-A-0 678 503.

[0107] The compounds of formula XV are obtainable by reacting forexample carbonic esters or derivatives of formula R₄CH₂COOR₁₁ with1,3-dihalogenpropene in the presence of strong amine bases such asalkali metal amides (Li-N(i-propyl)₂ or lithium hexamethyldisilazane) toform compounds of formula XV, or by preparing through derivatization ina manner known per se carboxylic acids, carboxylic acid halogenides,carboxamides and carboxylic acid salts from e.g. the carbonic esters offormula XV. The desired enantiomers can be obtained from the racematesin a manner known per se by separating the racemates, for example bycrystallization from addition salts of carboxylic acids using opticallyactive bases. It is more advantageous to separate the racemates bytreating esters of formula XV with esterases.

[0108] With the choice of carbonic esters and carboxylic acids offormulae IV and V, the compounds of formula I, which per se are complexcompounds, can be prepared in a convergent and simple manner, which isespecially true for this enantioselective or diastereoselectivesynthesis. The total yield from all process steps a) to h) may amount to40% or more, which makes industrial application feasible.

[0109] The following examples explain the invention in more detail.

[0110] A) Preparation of Compounds of Formula IV

EXAMPLE A1

[0111]

[0112] A mixture of 9.75 g magnesium powder and 100 ml tetrahydrofuranis heated to reflux, and 0.50 ml 1,2-dibromoethane then added over aperiod of 1 minute (visible exothermic reaction). A solution of 34.63 gA′, 3.80 ml 1,2-dibromoethane and 300 ml tetrahydrofuran is addeddropwise over a period of 30 minutes at 62-64° C. The mixture isagitated for another 30 minutes under reflux and then cooled down toambient temperature. The reaction mixture is filtered under argon untilclear and the resulting Grignard solution added dropwise over a periodof 10 minutes to a solution of 20.47 g A1, 0.24 ml N-methylpyrrolidone,0.88 g iron(III) acetylacetonate in 230 ml tetrahydrofuran at −5 to 0°C. The reaction mixture is stirred for a further 1 minute at 0° C., and400 ml 2N hydrochloric acid is then added. The mixture is now extractedwith diethyl ether (3×300 ml) and the organic phases washedconsecutively with water (1×300 ml) and saturated aqueous sodiumchloride solution (1×200 ml). The combined organic phases are dried oversodium sulfate, filtered and concentrated by evaporation on a Rotavapor.By means of flash chromatography (SiO₂ 60F; diethyl ether/hexane 1:4),title compound B1 is obtained from the residue as a slightly yellowishoil (33.8 g, 75%): TLC R_(t)=0.15 (diethyl ether-hexane 1:4). ¹H-NMR(300 MHz, CDCl₃): δ 0.75-0.9 (m, 12H), 1.15 (t, 3H), 1.40 (m, 1H), 1.60(m, 1H), 1.70-2.45 (m, 10H), 3.30 (s, 3H), 3.50 (t, 2H), 3.80 (s, 3H),3.90-4.10 (m, 4H), 5.25 (m, 2H), 6.60 (m, 2H), 6.70 (d, 1H) ppm.

EXAMPLE A2

[0113] By analogy with example A1, the derivative is prepared byreacting A′ with A2:

[0114]¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.00 (m, 12H), 1.40-2.55 (m, 12H),3.40 (s, 3H), 3.60 (t, 2H), 3.65 (s, 3H), 3.85 (s, 3H), 4.15 (t, 2H),5.40 (m, 2H), 6.65-6.75 (m, 2H), 6.80 (d, 1H) ppm.

EXAMPLE A3

[0115] A mixture of 38.9 g magnesium powder and 400 ml tetrahydrofuranis heated to reflux, and 2.0 ml 1-bromo-2-chloroethane then added over aperiod of 1 minute (visible exothermic reaction). A solution of 126-0.8g A1, 14.6 ml 1-bromo-2-chloroethane and 700 ml tetrahydrofuran is addeddropwise over a period of 35 minutes at 62-64° C. The mixture is stirredfor another 30 minutes under reflux and then cooled down to ambienttemperature. The reaction mixture is filtered under argon until clearand the resulting Grignard solution added dropwise over a period of 20minutes to a solution of 80.3 g A2, 5.58 ml triethylamine, and 2.11 gNidppeCl₂ in 700 ml tetrahydrofuran at 20 to 22° C. The reaction mixtureis stirred for a further 1 minute at 20° C., and 1 l 1N hydrochloricacid is then added, at 15° C. Extraction is now performed withtert-butyl methyl ether (2×1 l), and the organic phases are washedconsecutively with saturated aqueous sodium chloride solution/water(1:9) (2×1.2 l) and saturated aqueous sodium chloride solution (1×300ml). The combined organic phases are dried over sodium sulfate, filteredand concentration by evaporation on a rotary evaporator. A2 which hasnot been converted is distilled off from the residue at 75° C. under avacuum. Crude title compound B2 obtained in this way (171.4 g) isfurther reacted in example B2.

[0116] B) Preparation of Compounds of Formula V

Example B1 Preparation of Carboxylic Acid

[0117]

[0118] To a solution of 22.4 g B1 and 150 mltetrahydrofuran/methanol/water (3:1:1) 3.6 g lithium hydroxide is addedand then stirred for 48 hours under reflux. The reaction mixture isconcentrated by evaporation, 500 ml 1N HCl (cold) is added to theresidue, and extraction performed with tert-butyl methyl ether (3×500ml). The organic phases are washed with saturated, aqueous NaCl solution(200 ml), dried over sodium sulfate and concentrated on a rotaryevaporator. By means of flash chromatography (SiO₂ 60F/ethylacetate/hexane 1:1), title compound Cl is obtained from the residue as aslightly yellowish oil (19.2 g, 94%):TLC R_(t)=0.22 (diethylether-hexane 2:1).

[0119]¹H-NMR (300 MHz, CDCl₃): δ 0.80-1.0 (m, 12H), 1.50 (m, 1H), 1.70(m, 1H), 1.80-2.60 (m, 10H), 3.40 (s, 3H), 3.65 (t, 2H), 3.85 (s, 3H),4.15 (m, 2H), 5.45 (n, 2H), 6.70 (m, 2H), 6.80 (d, 1H) 7.60-9.0 (bs, 1H)ppm.

[0120] Title compound C1 can be prepared from B2 by analogy with exampleB1.

EXAMPLE B2 Preparation of Carboxylic Acid-Cyclohexylamine Salt

[0121]

[0122] To a solution of 171.4 g (crude) B2 and 1.07 l dioxane, 0.67 lwater and 0.4 l 2N KOH are added and the mixture is then stirred underreflux for 23 hours. The reaction mixture is concentrated byevaporation, 0.6 l water is added to the residue which is washed withtert-butyl methyl ether (2×500 ml) (organic phases are discarded). Theaqueous phase is acidified with 0.24 l 4N HCl and then extracted withtert-butyl methyl ether (2×0.6 l). The organic phases are washed withaqueous NaCl solution (0.6 l), dried over sodium sulfate andconcentrated on a rotary evaporator. The residue is dissolved in 2 ln-hexane, 38.5 ml cyclohexylamine is added and the mixture stirred for20 hours at room temperature. The resulting suspension is cooled to 0°C., and title compound C2 is obtained by filtration in the form of whitecrystals (165.6 g, 79.6%)

[0123] C) Preparation of Compounds of Formula VI

EXAMPLE C1 Preparation of

[0124]

[0125] A solution of 2.66 g C1 and 26.6 ml dichloromethane is cooled to−15° C. Then 4×0.232 g N-bromosuccinimide is added in portions every 2minutes. The reaction mixture is stirred for another 30 minutes at −15°C. and then, over a period of 5 minutes, is introduced to 30 ml of 40%sodium hydrogen sulfite solution cooled to 0° C. The mixture is dilutedwith water (10 ml) and extracted with dichloromethane (2×30 ml). Theorganic phases are washed consecutively with water (1×30 ml) andconcentrated aqueous NaCl solution (1×30 ml), then dried over sodiumsulfate and concentrated on a rotary evaporator. By means of flashchromatography (SiO₂ 60F/diethyl ether/hexane 1:1) 2.98 g title compoundD1 is obtained from the residue (content of title compound=approx. 89%);TLC R_(t)=0.34 (cis-lactone) and 0.38 (trans-lactone) with diethylether/hexane 2:1.

[0126]¹H-NMR (300 MHz, CDCl₃): δ 0.85-1.10 (m, 12H), 1.60-2.65 (m, 12H),3.40 (s, 3H), 3.60 (t, 2H), 3.55-3.70 (m, 1H), 3.85 (s, 3H), 4.15 (t,2H), 4.25 (m, 1H), 6.70-6.85 (m, 3H) ppm.

EXAMPLE C2 Preparation from Carbonic Ester B1 in the Presence of Water

[0127] A solution of 0.449 g B 1, 3.3 ml tetrahydrofuran and 1.7 mlwater is cooled to 0° C. 0.205 g N-bromosuccinimide is added to thesolution and the mixture stirred for 30 minutes at 0° C. and for 15hours at 70° C. The reaction mixture is cooled to 0° C. and added to 30ml of 40% aqueous sodium hydrogen sulfite solution that has been cooledto 0° C. The mixture is extracted with ethyl acetate (3×50 ml). Theorganic phases are washed consecutively with water (1×30 ml) andconcentrated aqueous NaCl solution (1×30 ml), dried over sodium sulfateand concentrated on a rotary evaporator. By means of flashchromatography (SiO₂ 60F/diethyl ether/hexane 1:1) 0.42 g title compoundD1 is obtained from the residue (content of title compound=approx. 80%);TLC R_(t)=0.34 (cis-lactone) and 0.38 (trans-lactone) with diethylether/hexane 2:1.

[0128]¹H-NME (300 MHz, CDCl₃): δ 0.85-1.10 (m, 12H), 1.60-2.65 (m, 12H),3.40 (s, 3H), 3.60 (t, 2H), 3.55-3.70 (m, 1H)), 3.85 (s, 3H), 4.15 (t,2H), 4.25 (m, 1H), 6.70-6.85 (m, 3H) ppm.

EXAMPLE C3 Preparation from Cyclohexylamine Salt C2

[0129] A solution of 164.3 g C2 and dichloromethane is cooled to 0° C.26.6 ml trifluoroacetic acid is added drop by drop and the mixturestirred for 1 hour. The reaction mixture is cooled to −20° C. Then6×9.38 g N-bromosuccinimide is added in portions every 2 minutes. Thereaction mixture is stirred for a further 2 hours at −15 to −20° C., and160 ml 4% aqueous sodium hydrogen sulfite solution then added at 0° C.The mixture is extracted with water (1 l) and the organic phaseseparated off. The aqueous phase is extracted with dichloromethane (0.5l) and the combined organic phases washed with water (1 l) and aqueousNaCl solution (0.5 l), then dried over sodium sulfate and concentratedon a rotary evaporator. The crude title compound DI obtained in this way(161.4 g) (content of title compound approx. 90%) is further reacted inexamples D2 and E2.

[0130] D) Preparation of Compounds of Formula VII

EXAMPLE D1 Preparation of

[0131]

[0132] A solution of 16.65 g D1 and 150 ml isopropanol is cooled to 0°C., then 66.6 ml 2N LiOH is added over a period of 10 minutes and themixture stirred for 1.5 hours (the intermediate E1 is immediatelyreacted further in the next step).

EXAMPLE D2

[0133] Compound E1 is obtained in an analogous manner using compound D1prepared as described under example C3 and is used in example E2.

E) Preparation of Compounds of Formula VIII EXAMPLE E1 Preparation of

[0134]

[0135] To the reaction mixture of example D1, 100 ml 2N HCl is addeddrop by drop, and the reaction mixture is stirred for 1 hour at roomtemperature. The reaction mixture is diluted with water (500 ml) andextracted with tert-butyl methyl ether (3×250 ml). The organic phasesare washed consecutively with water (2×500 ml) and concentrated aqueousNaCl solution (200 ml), dried over sodium sulfate and concentrated on arotary evaporator. By means of flash chromatography (SiO₂ 60F/diethylether/hexane 2:1) 12.0 g title compound F1 is obtained from the residue(content of title compound=approx. 88%); TLC R_(t)=0.16 (diethylether/hexane 2:1). ¹H-NMR (300 MHz, CDCl₃): δ 0.80-1.05 (m, 12H),1.10-2.25 (m, 10H), 2.35 (m, 1H), 2.50-2.75 (m, 2H), 3.40 (s, 3H), 3.60(t, 2H), 3.90 (s, 3H), 3.80-3.90 (m, 1H), 4.15 (t, 2H), 4.25 (m, 1H),6.70-6.85 (m, 3H) ppm.

EXAMPLE E2

[0136] The stirred mixture of 161.4 g D1. (crude), 1.61 ltetrahydrofuran and 0.474 l water is stirred at room temperature for 20h with 0.474 l 2N LiOH. Then 1.61 l water is added and thetetrahydrofuran (1.7 l) evaporated off on a rotary evaporator. Theresulting mixture is washed with tert-butyl methyl ether (0.5 l) and theaqueous solution of the intermediate E1 is obtained and immediatelyreacted further. While stirring, tert-butyl methyl ether (1.0 l) and 4NHCl (0.316 l) are added. The organic phase is separated off and stirredfor 2 hours under reflux (with a water separator). The solution iscooled, dried over sodium sulfate and concentrated on a rotaryevaporator. The crude title compound F1 obtained in this way (136.1 g)(content of title compound approx. 90%) is further reacted in exampleF4.

[0137] F) Preparation of Compounds of Formula IX

EXAMPLE F1 Preparation of

[0138]

[0139] wherein R₁₂ is CH₃—SO₂—(G1).

[0140] To a solution of 0.325 g F1 and 8 ml dichloromethane, 0.156 mltriethylamine is added and the mixture cooled to 0° C. 0.087 mlmethanesulfonyl chloride is added drop by drop and the mixture thenstirred for 1 hour at room temperature. The reaction mixture is pouredonto water (10 ml) and extracted with tert-butyl methyl ether (2×10 ml).The organic phases are washed consecutively with 5% aqueous sodiumhydrogencarbonate solution (10 ml) and concentrated aqueous NaClsolution (10 ml). The combined organic phases are dried over sodiumsulfate and concentrated by evaporation on a rotary evaporator. By meansof flash chromatography (SiO₂ 60F/diethyl ether/hexane 2:1), titlecompound GC is obtained from the residue as a slightly yellowish oil(0.32 g, 82%) TLC R_(t)=0.18 (diethyl ether-hexane 2:1) ¹H-NMR (300 MHz,CDCl₃): δ 0.85-1.05 (m, 12H), 1.55-2.25 (m, 9H), 2.40 (m, 1H), 2.60 (m,1H), 2.75 (m, 1H), 2.95 (s, 3H), 3.40 (s, 3H), 3.60 (t, 2H), 3.85 (s,3H), 4.15 (t, 2H), 4.45 (m, 1H), 4.80 (m, 1H), 6.70-6.85 (m, 3H) ppm.

EXAMPLE F2 Preparation of

[0141]

[0142] wherein R₁₂ is 4-BrC₆H₅—SO₂— (G2)

[0143] To a solution of 0.437 g F1 and 5 ml dichloromethane, 0.307 g4-bromobenzenesulfochloride and 0.147 g 4-dimethylaminopyridine areconsecutively added and the mixture then stirred for 24 hours at roomtemperature. The reaction mixture is poured onto iced water (30 ml) andextracted with diethyl ether (3×30 ml). The organic phases are washedconsecutively with 5% aqueous sodium hydrogencarbonate solution (30 ml)and concentrated aqueous NaCl solution (30 ml). The combined organicphases are dried over sodium sulfate and concentrated by evaporation ona rotary evaporator. By means of flash chromatography (SiO₂ 60F/diethylether/hexane 1:1), title compound G2 is obtained from the residue as aslightly yellowish oil (0.304 g, 46%): TLC R_(t)=0.36 (diethylether-hexane 2:1).

[0144]¹H-NMR (300 MHz, CDCl₃): δ 0.80-1.0 (m, 12H), 1.55-2.20 (m, 9H),2.25-2.45 (m, 2H), 2.70 (m, 1H), 3.40 (s, 3H), 3.60 (t, 2H), 3.90 (s,3H), 4.15 (m, 2H), 4.35 (m, 1H), 4.65 (m, 1H), 6.60-6.85 (m, 3H),7.60-7.75 (m, 4H) ppm.

EXAMPLE F3 Preparation of

[0145]

[0146] wherein R₁₂ is 4-CH₃C₆H₅—SO₂— (G3).

[0147] To a solution of 0.437 g F1 and 5 ml dichloromethane, 0.229 g4-methylbenzenesulfochloride and 0.147 g 4-dimethylaminopyridine areadded and the mixture then stirred for 24 hours at room temperature. Thereaction mixture is poured onto iced water (30 ml) and extracted withdiethyl ether (3×30 ml). The organic phases are washed consecutivelywith 5% aqueous sodium hydrogencarbonate solution (30 ml) andconcentrated, aqueous NaCl solution (30 ml). The combined organic phasesare dried over sodium sulfate and concentrated by evaporation on arotary evaporator. By means of flash chromatography (SiO₂ 60F/diethylether/hexane 1:1), title compound G3 is obtained from the residue as aslightly yellowish oil (0.40 g, 68%) TLC R_(t)=0.26 (diethylether-hexane 2:1).

[0148]¹H-NMR (300 MHz, CDCl₃): (0.80-1.0 (m, 12H), 1.55-2.20 (m, 9H),2.30-2.50 (m, 2H), 2.45 (s, 3H), 2.65 (m, lH), 3.40 (s, 3H), 3.60 (t,2H), 3.90 (s, 3H), 4.15 (m, 2H), 4.35 (m, 1H), 4.70 (m, 1H), 6.60-6.85(m, 3H), 7.35 (d, 2H), 7.70 (d, 2H) ppm.

EXAMPLE F4 Preparation of G1

[0149] To a solution of 136.1 g F 1 (crude), prepared as described inexample E2, and 0.86 l toluene, 52.8 ml triethylamine is added and themixture cooled to 0° C. 29.45 ml methanesulfonyl chloride is added dropby drop and the mixture then stirred for 1 hour at 15° C. The reactionmixture is cooled to 0° C., 7.88 ml 3-dimethylamino-1-propylamine isadded (the excess of methanesulfonylchloride is destroyed) and themixture stirred for 15 minutes. The reaction mixture is washed withwater (1 l), the organic phase separated off and the aqueous phaseextracted again with toluene (0.6 l). The organic phases are washedconsecutively with water/saturated NaCl solution (5:1; 0.6 l) andsaturated aqueous NaCl solution (0.6 l), dried over sodium sulfate andconcentrated on a rotary evaporator. The crude title compound F1obtained in this way (165 g) (content of title compound approx. 90%) isfurther reacted in example G2.

[0150] G) Preparation of Compounds of Formula II

EXAMPLE G1 Preparation of

[0151]

[0152] A mixture of 9.5 g G1, 2.35 g sodium azide and 100 ml1.3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone is stirred for 20 hoursat 60° C. The reaction mixture is poured onto 500 ml water and extractedwith tert-butyl methyl ether (3×200 ml). The organic phases are washedconsecutively with water (3×500 ml), 5% aqueous sodium hydrogencarbonatesolution (200 ml) and concentrated aqueous NaCl solution (200 ml). Thecombined organic phases are dried over sodium sulfate and concentratedon a rotary evaporator. By means of crystallization from 150 mldiisopropylether-hexane (1:2) at 0° C., title compound H1 is obtainedfrom the residue as white crystals (5.62 g, 67%); m.p. 61-620 C; TLCR_(t)=0.41 (ethyl acetate-hexane 1:1); ¹H-NMR (300 MHz, CDCl₃): δ0.85-1.10 (m, 12H), 1.40 (m, 1H), 1.60-2.25 (m, 8H), 2.45 (m, 1H), 2.60(m, 2H), 2,95 (m, 1H), 3,40 (s, 3H), 3.60 (t, 2H), 3.85 (s, 3H), 4.15(t, 2H), 4.30 (m, 1H)), 6.70-6.85 (m, 3H) ppm.

[0153] Derivative H1 can be prepared by reaction of G2 or G3 by analogywith example G1.

EXAMPLE G2 Preparation of H1

[0154] A mixture of 165 g Gi (crude), 41.1 g sodium azide and 0.8 l1.3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone is stirred for 20 hoursat 60° C. The reaction mixture is cooled, poured onto 1.5 l water andextracted with methylcyclohexane (2×750 ml). The organic phases arewashed consecutively with water (4×750 ml) and concentrated aqueous NaClsolution (750 ml). The combined organic phases are dried over sodiumsulfate and concentrated to a volume of 900 ml on a rotary evaporator.The resulting solution is inoculated with 10 mg of title compound andstirred for 20 hours at ambient temperature. The resulting suspension iscooled to 0° C., and title compound H1 is obtained by filtration in theform of white crystals (104 g, 71%)

EXAMPLE G3 Preparation of H1

[0155] A mixture of 10.3 g G1 (crude), 50 ml methylcyclohexane, 40 ml 2Nsodium azide (aqueous solution) and 0.4 g Aliquat® is stirred for 20 hat 80° C. The reaction mixture is cooled to 40° C., the aqueous phase isseparated off and the organic phase washed at 40° C. with (2×40 ml). Theorganic phase is dried over sodium sulfate and filtered. The filtrate isinoculated with 5 mg of title compound and stirred for 20 hours atambient temperature. The resulting suspension is cooled to 0° C., andtitle compound Hi is obtained by filtration in the form of whitecrystals (6.60 g, 71%).

[0156] H) Preparation of Compounds of Formula III

EXAMPLE H1 Preparation of

[0157]

[0158] A mixture of 59.1 g H1, 41.82 g3-amino-2,2-dimethyl-propionamide, 2.28 g 2-hydroxypyridine in 59.1 mltriethylamine is stirred over a period of 16 hours at 90° C. Then 33 mltriethylamine is distilled off over a period of 0.5 hours, and theresidue is agitated for a further 8.5 hours at 90° C. The cooledreaction mixture is extracted between ethyl acetate (3×500 ml),saturated aqueous sodium hydrogencarbonate solution (1×500 ml) andsaturated sodium chloride solution (1×500 ml). The combined organicphases are dried with 100 g sodium sulfate, filtered and concentrated onthe rotary evaporator. The residue is dried and crude title compound F1is obtained as an oil (78.4 g, quantitative) (HPLC assay: 88.5%): TLCR_(t)=0.13 (ethyl acetate-hexane 4:1); chromatographed sample: TLCR_(t)=0.13 (ethyl acetate/hexane 4:1); ¹H-NMR (500 MHz, CDCl₃, δ):0.85-0.96 (m, 12H), 1.23 (s, 6H), 1.30-1.40 (m, 1H), 1.53-1.80 (m, 5H),1.82-1.93 (m, 1H), 2.06-2.14 (m, 3H), 2.45-2.57 (m, 2H), 2.87-2.92 (m,1H), 3.13 (d, 1H), 3.32-3.52 (m, 3H), 3.36 (s, 3H), 3.59 (t, 2H), 3.84(s, 3H), 4.12 (t, 2H), 5.51 (bs, 1H), 6.01 (bs, 1H), 6.43 (t, 1H), 6.72(dd, 1H), 6.75 (d, 1H), 6.81 (d, 1H) ppm.

EXAMPLE H2 Preparation of J1

[0159] A mixture of 9.23 q H1, 6.97 g 3-amino-2,2-dimethylpropionamide,1.90 g 2-hydroxypyridine and 5.0 ml triethylamine is stirred over aperiod of 24 hours at 65° C. The cooled reaction mixture is extractedbetween tert-butyl methyl ether (2×150 ml) and water (2×150 ml). Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated on a rotary evaporator. The residue is dried and crudetitle compound Fl is obtained as an oil (11.65 g, quantitative) (HPLCassay: >95%).

EXAMPLE H3 Preparation of J1

[0160] A mixture of 4.62 g H1, 3.48 g 3-amino-2,2-dimethylpropionamideand 0.95 g 2-hydroxypyridine is stirred over a period of 24 hours at 65°C. The cooled reaction mixture is extracted between tert-butyl methylether (2×100 ml) and water (2×100 ml). The combined organic phases aredried over sodium sulfate, filtered and concentrated on a rotaryevaporator. The residue is dried and crude title compound J1 isobtained. as an oil (5.75 g, quantitative) (HPLC assay: >95%).

[0161] J) Hydrogenation of the Azide Group to Form Compounds of FormulaI

EXAMPLE J1 Preparation of

[0162]

[0163] 78.4 g (HPLC assay: 88.5%) J1 (crude) is hydrogenated for 3 hoursin the presence of 3.92 g Pd/C 5% and 7.2 ml ethanolamine in 700 mltert-butyl methyl ether at ambient temperature and 3.0 bar. The reactionmixture is filtered and the catalyst washed with 300 ml tert-butylmethyl ether. The filtrate is washed consecutively with 400 ml 2N NaOHand 400 ml brine. The aqueous phases are then extracted with tert-butylmethyl ether (2×400 ml). The combined organic phases are dried with 100g sodium sulfate and concentrated by evaporation. The residue is mixedwith 7.31 g fumaric acid and dissolved in 200 ml ethanol and filtereduntil clear. The filtrate is concentrated by evaporation to a totalweight of 104 g and dissolved in 1.7 l acetonitrile at 35° C. Theresulting solution is inoculated with 10 mg of title compound(hemifumarate) and stirred for 17 hours at ambient temperature. Thesuspension is cooled to 0° C. and filtered off by suction after 2 hours.The residue is washed with acetonitrile (3×200 ml) and then dried in avacuum at 35° C. The title compound K1 (hemifumarate) is obtained aswhite crystals (59.5 g, 81% in relation to J1): 1H NMR (360 MHz,DMSO-d₆); δ 0.7-0.9 (m, 12H), 1.04 (s, 6H), 1.27 (m, 3H), 1.4-1.8 (m,4H), 1.94 (m, 2H), 2.23 (m, 1H), 2.35 (dd, J 8.4, 8.0 Hz, 1H), 2.45 (m,1H), 3.08 (m, 2H), 3.2-3.5 (m, 2H), 3.24 (s, 3H), 3.47 (t, J=6.4 Hz,2H), 3.74 (s, 3H), 3.97 (t, J=6.4 Hz, 2H), 6.37 (s, 1H), 6.68 (dd,J=8.0, 2.0 Hz, 1H), 6.77 (d, J=6 Hz, 1H), 6.80 (bs, 1H), 6.83 (d, J=8Hz, 1H), 7.13 (bs, 1H), 7.49 (t, J=6 Hz, 1H).

What is claimed is:
 1. Process for preparation of compounds of formula I,

wherein R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, or C₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₅ is C₁-C₆alkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆-alkyl, C₁-C₆alkanoyloxy-C₁-C₆alkyl, C₁-C₆aminoalkyl, C₁-C₆alkylamino-C₁-C₆alkyl, C₁-C₆-dialkylamino-C₁-C₆-alkyl, alkanoylamido-C₁-C₆-alkyl, HO(O)C—C₁-C₆-alkyl, C₁-C₆alkyl-O—(O)C—C₁-C₆alkyl, H₂N—C(O)—C₁-C₆alkyl, C₁-C₆alkyl-HN—C(C)—C₁-C₆alkyl or (C₁-C₆alkyl)₂N—C(O)—C₁-C₆-alkyl, a) by reacting a compound of formula II,

 with an amine of formula R₅—NH₂ to form a compound of formula III,

 and b) by reducing the azide group of the compound of formula III to the amine group and isolating the compounds of formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of compounds of formula II by c1) reacting a compound of formula IV,

 wherein R₆ is C₁-C₂₀alkyl, C₃-C₁₂cycloalkyl, C₃-C₁₂cycloalkyl-C₁-C₆alkyl, C₆-C₁₀aryl or C₆-C₁₀-aryl-C₁-C₆alkyl, with a halogenation agent to form a compound of formula VI, or c2) reacting a carboxylic acid of formula V, or a salt of this carboxylic acid,

 with a halogenation agent to form a compound of formula VI,

 wherein X is Cl, Br or I, d) reacting the compound of formula VI in the presence of an alkali metal or alkaline earth metal hydroxide or an alcohol to form a compound of formula VII,

 wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group, e) hydrolysing the compound of formula VII in the presence of an acid to form a compound of formula VIII,

f) substituting the hydrogen atom of the hydroxyl group in the compound of formula VIII and converting it to a leaving group AO to form compounds of formula IX,

g) and then reacting the compound of formula IX with an azidation agent to form a compound of formula II, or h) reacting the compound of formula VIII directly with a zinc azide/-bis-pyridine complex in the presence of a tertiary phosphine and an azodicarboxylate, if necessary in an organic solvent, to form a compound of formula II.
 2. A process according to claim 1 comprising an embodiment wherein R₁ is C₁-C₄alkoxy or C₁-C₄alkoxy-C₁-C₄alkyloxy, R₂ is C₁-C₄alkoxy, R₃ is C₁-C₄alkyl, R₄ is C₁-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl which if necessary is N-monosubstituted or N-di-C₁-C₄alkyl substituted.
 3. A process according to claim 2 comprising an embodiment wherein R₁ is 1-methoxyprop-3-yloxy and R₂ is methoxy.
 4. A process according to claim 2 comprising an embodiment wherein R₃ and R₄ are in each case isopropyl.
 5. A process according to claim 2 comprising an embodiment wherein R₅ is H₂NC(O)—C₁-C₆alkyl.
 6. A process according to claim 1 comprising an embodiment wherein R₁ is methoxy-C₂-C₄alkyloxy, R₂ is methoxy or ethoxy, R₃ is C₂-C₄alkyl, R₄ is C₂-C₄alkyl and R₅ is H₂NC(O)—C₁-C₆alkyl.
 7. A process according to claim 1 comprising an embodiment wherein R₁ is 3-methoxy-prop-3-yloxy, R₂ is methoxy, R₃ and R₄ are each 1-methyleth-1-yl, and R₅ is H₂NC(O)—[C(CH₃)₂]—CH₂—.
 8. Compounds of formula X,

wherein R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, or C₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, and R₈ is hydrogen or R₈O is a leaving group.
 9. Compounds of formula VII,

wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group, and R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, or C₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, and R₄ is C₁-C₆alkyl.
 10. Compounds of formula XIII,

wherein R₁₁ is an alkali metal, an equivalent alkaline earth metal, hydrogen or the residue of an alcohol minus a hydroxyl group, and R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, or C₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, and R₄ is C₁-C₆alkyl. 